Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran.

Background: Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of diabetes characterized by noninsulin-dependent, autosomal-dominant disorder with strong familial history, early age of onset, and pancreatic beta-cell dysfunction. Mutations in at least 14 different genes are responsible for various MODY subtypes. Heterozygous mutations in the hepatocyte nuclear factor 1 alpha () gene are responsible for the MODY3 subtype, which is a common subtype of MODY in different studied populations. To date, more than 450 different variants of this gene have been reported as disease causing for MODY3. This study was carried out to evaluate mutations in Iranian diabetic families fulfilling MODY criteria.

Materials And Methods: Polymerase chain reaction and Sanger sequencing were performed. All the ten exons of the gene were sequenced in ten families, followed by cosegregation analysis and evaluation. Computational protein modeling was accomplished for the identified mutation.

Results: MODY3 was confirmed in two large families by detecting a mutation (p.G253E) in coding regions of . Compound heterozygous state for two common variants in (p.I27 L and p.S487N) was detected in affected members of 5 families, and in one family, a rare benign variant in the coding sequence for Kozak sequence was detected. Two new nonpathogenic variants were found in noncoding regions of .

Conclusion: It seems that mutations are a common cause of MODY in Iranian diabetic patients. Identified common variants in heterozygous state can cause diabetes Type II in earlier ages. The role of rare variant rs3455720 is unknown, and more investigation is needed to uncover the function of this variant.